1. Field of the Invention
The present invention relates to novel substituted benzylurea derivatives or salts thereof, and medicines comprising such a derivative as an active ingredient, and particularly to substituted benzylurea derivatives or salts thereof, which are useful as antiarteriosclerotic agents which selectively inhibit an acyl-coenzyme A cholesterol acyltransferase (ACAT) in macrophages present in an artery wall, thereby preventing formation of foam cells, and medicines comprising such a derivative as an active ingredient.
2. Description of the Background Art
Cardiac diseases and cerebrovascular diseases stand second and third, respectively, to cancers in Japan as regards the causes of death, and are more than half the number of the causes of death if both are put together. Most of these diseases occur as a terminal symptom of arteriosclerosis. The arteriosclerosis is also caused by aging and has no general diagnosis. Besides, the name of a disease called arteriosclerosis is also not present. However, it is considered that the mortality from arteriosclerosis is very high.
With respect to the mechanism attacked by arteriosclerosis, there have been many unknown points. Many researches have been conducted in this mechanism, and the mechanism has been rapidly elucidated in recent years. More specifically, when arteriosclerosis occurs, an atherosclerotic lesion, in which cholesteryl esters are accumulated in plenty, is formed. With the growth of this lesion, the constriction of a vascular lumen progresses, resulting in complete obstruction of the vessel in the worst case. As described above, the arteriosclerosis is a very horrible disease. As a method for treating and preventing arteriosclerosis, a method of lightening risk factors dominates up to the present. This method is a method in which exacerbation factors participating in the attack of arteriosclerosis are removed. More specifically, in addition to dietetic therapy, there are many useful therapeutic and prophylactic methods such as methods of administering various kinds of serum lipid-reducing agents and antihypertensive drugs. However, the action of these drugs on arteriosclerosis is indirect, and so there is a strong demand for development of drugs which directly act on arteriosclerosis.
An ACAT inhibitor is one of the proposed drugs having such direct action. ACAT is an enzyme that acylates cholesterol to synthesize an accumulation type cholesteryl ester. In the atherosclerotic lesion in arteriosclerosis, this cholesteryl ester is accumulated in excess. It is therefore expected that the inhibition of ACAT can prevent an excess of accumulation of the cholesteryl ester, and also the growth of the sclerotic lesion.
The conventional ACAT inhibitors include compounds described in Japanese Patent Application Laid-Open Nos. 117651/1990, 234839/1992 and 7259/1991, "H. Tawara et al., J. Med. Chem., 37, 2079-2084 (1994)", and Japanese Patent Application Laid-Open Nos. 41006/1996 and 258200/1995. These documents investigate inhibitory activities against ACAT in small intestine microsomes or liver microsomes, or an action that cholesterol in plasma is indirectly reduced, but do not describe anything about inhibitory activities against ACAT in macrophages that are considered to be more important when investigating an anti-arteriosclerotic action.
Further, in compounds described in "Thomas P. Maduskuie, Jr. et al., J. Med. Chem., 38, 1067-1083 (1995)", those that more strongly inhibit ACAT in macrophages compared with ACAT in liver microsomes are also found. However, it cannot be said that their selective effects are sufficient.